Soybean Seeds (Glycine max L.) Extract Against Cytokine Storm in ARDS Rat Model through Inhibiting Inflammation Marker

Several studies have suggested that "cytokine storms" are significant causes of the severity of COVID-19. Controlling and inhibiting the cytokine storm in COVID-19 could prevent the spread of COVID-19 and saves patient lives. Soybean (Glycine max L.) is known to have various biological activities. This study aims to examine bioactive compounds in SSE and the effect of SSE on the ARDS rats model. A total of 25 Sprague Dawley Lipopolysaccharide-induced rats were used. Determination of serum IL-1β, IL-12, and lung TNF-α levels was performed by ELISA method. NF-κB and IFN-γ expression were determined by the qRTPCR method. IL-6 expressions were analyzed by immunohistochemistry assay. The bleeding, inflammation, and alveolus collapse score were analyzed using the HE staining method. The results showed that SSE could decrease the level of IL-1β, IL-12, TNF-α, IL-6, NF-kB, and IFN-γ and improve the bleeding, inflammation, and alveolus score in the lung. SSE could decrease the pro-inflammatory cytokines and improve lung condition in ARDS rats model. © 2023, Bogor Agricultural University. All rights reserved.

Photobiomodulation Reduces the Cytokine Storm Syndrome Associated with COVID-19 in the Zebrafish Model.

Although the exact mechanism of the pathogenesis of coronavirus SARS-CoV-2 (COVID-19) is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the level of inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red photobiomodulation (PBM) as an attractive therapy to downregulate the cytokine storm caused by COVID-19 in a zebrafish model. RT-qPCR analyses and protein-protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that recombinant Spike protein (rSpike) was responsible for generating systemic inflammatory processes with significantly increased levels of pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a and coa1) mRNA markers, with a pattern similar to those observed in COVID-19 cases in humans. On the other hand, PBM treatment was able to decrease the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most-impacted metabolic pathways between PBM and the rSpike treated groups were related to steroid metabolism, immune system, and lipid metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19 and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials can commence.

The potential for traditional Chinese therapy in treating sleep disorders caused by COVID-19 through the cholinergic anti-inflammatory pathway.

Since the outbreak of Coronavirus disease (COVID-19) in 2019, it has spread rapidly across the globe. Sleep disorders caused by COVID-19 have become a major concern for COVID-19 patients and recovered patients. So far, there's no effective therapy on this. Traditional Chinese therapy (TCT) has a great effect on sleep disorders, with rare side effects and no obvious withdrawal symptoms. The cholinergic anti-inflammatory pathway, a neuroregulatory pathway in the central nervous system that uses cholinergic neurons and neurotransmitters to suppress inflammatory responses, has been reported to be associated with sleep disorders and psychiatric symptoms. Many studies have shown that TCT activates the cholinergic anti-inflammatory pathway (CAP), inhibits inflammation, and relieves associated symptoms. Therefore, we believe that TCT may be a potential therapeutic strategy to alleviate sleep disorders induced by COVID-19 through CAP. In this review, we analyzed the relationship between cytokine storm induced by Coronavirus and sleep disorders, explained the influence of CAP on sleep disorders, discussed the TCT's effect on CAP, and summarized the treatment effect of TCT on sleep disorders. Based on these practical researches and theoretical basis, we propose potential strategies to effectively improve the sleep disorders caused by COVID-19.

Current understanding on long non-coding RNAs in immune response to COVID-19.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic threatening the lives and health of people worldwide. Currently, there are no effective therapies or available vaccines for COVID-19. The molecular mechanism causing acute immunopathological diseases in severe COVID-19 is being investigated. Long noncoding RNAs (lncRNAs) have been proven to be involved in many viral infections, such as hepatitis, influenza and acquired immune deficiency syndrome. Many lncRNAs present differential expression between normal tissue and virus-infected tissue. However, the role of lncRNAs in SARS-CoV-2 infection has not been fully elucidated. This study aimed to review the relationship between lncRNAs and viral infection, interferon and cytokine storms in COVID-19, hoping to provide novel insights into promising targets for COVID-19 treatment.

Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients.

BACKGROUND: There is still insufficient knowledge with regard to the potential involvement of mast cells (MCs) and their mediators in the pathology of coronavirus disease-2019 (COVID-19). Therefore, our study aimed to investigate the role of MCs, their activation and protease profiles in the pathogenesis of early and late lung damage in COVID-19 patients. METHODS: Formalin-fixed and paraffin embedded lung specimens from 30 patients who died from COVID-19 and 9 controls were used for histological detection of MCs and their proteases (tryptase, chymase) followed by morphometric quantification. RESULTS: Our results demonstrated increased numbers of MCs at early stage and further augmentation of MCs number during the late stage of alveolar damage in COVID-19 patients, as compared to the control group. Importantly, the percentage of degranulated (activated) MCs was higher during both stages of alveolar lesions in comparison to the controls. While there was no prominent alteration in the profile of tryptase-positive MCs, our data revealed a significant elevation in the number of chymase-positive MCs in the lungs of COVID-19 patients, compared to the controls. CONCLUSIONS: MCs are characterized by dysregulated accumulation and increased activation in the lungs of patients suffering from COVID-19. However, future profound studies are needed for precise analysis of the role of these immune cells in the context of novel coronavirus disease.

Cytokine storm and stem cell activation in unveiling potential targets for diagnosis and therapy

Cytokine storms illustrate a robust, uncontrolled immune response that can severely disrupt the physiology of a person infected with a virus such as COVID-19. Cytokine storms during the most severe of COVID-19 infections are believed to be one of the major contributing factors to mortality and severe pathologic outcomes of the disease. Dysregulated levels of cytokines during a cytokine storm contribute to changes in different components of the local microenvironments including the stem cell components. Here, we review the pathophysiology of cytokine storms looking at different aspects of viral-induced cytokine release. In particular, we note the changes in the stem cell compartments that occur as well as therapeutic targets relying on targeting stem cells. © 2022 Elsevier Inc. All rights reserved.

Identification of Hub Genes and Key Pathways in TNF-α and IFN-γ Induced Cytokine Storms via Bioinformatics

Cytokine storms, an overaggressive immune response due to the overexpression of pro-inflammatory cytokines, have been identified to play a significant role in COVID-19 infections. Studies have shown that TNF-α and IFN-γ are integral to the process, however, its genetic mechanisms have yet to be fully elucidated. Herein, the key changes in the gene expression of TNF-α and IFN-γ induced cytokine storms are identified through differential gene analysis on the publicly available GEO GSE160163 dataset. GO and KEGG enrichment were used to annotate identified DEGs, and a PPI network was constructed based on the STRING database. A total of 446 differentially expressed genes were identified. Up-regulated genes and downregulated genes were enriched in viral immune response and infection pathways, and steroid biosynthesis and metabolic pathways, respectively. PPI construction revealed 1,834 interactions between 428 proteins, indicating their biological connectivity. Module analysis identified nine (9) hub genes: STAT1, CXCL10, CD274, CXCL9, IRF1, PSMB9, CD86, STAT3, and CXCR4, involved in viral immune response and three (3) significant modules involved in NOD-like receptor signaling, steroid biosynthesis, and viral infections. These identified DEGs, hub genes, and their respective enriched pathways aid us in understanding the molecular mechanisms of cytokine storms, as well as provide potential gene targets and druggable receptors for the treatment of cytokine storms. © 2022 IEEE.

Platelet-leukocyte crosstalk in COVID-19: How might the reciprocal links between thrombotic events and inflammatory state affect treatment strategies and disease prognosis?

Platelet-leukocyte crosstalk is commonly manifested by reciprocal links between thrombosis and inflammation. Platelet thrombus acts as a reactive matrix that recruits leukocytes to the injury site where their massive accumulation, activation and migration promote thrombotic events while triggering inflammatory responses. As a life-threatening condition with the associations between inflammation and thrombosis, COVID-19 presents diffuse alveolar damage due to exaggerated macrophage activity and cytokine storms. These events, together with direct intracellular virus invasion lead to pulmonary vascular endothelialitis, cell membranes disruption, severe endothelial injury, and thrombosis. The developing pre-alveolar thrombus provides a hyper-reactive milieu that recruits circulating leukocytes to the injury site where their activation contributes to thrombus stabilization and thrombosis propagation, primarily through the formation of Neutrophil extracellular trap (NET). NET fragments can also circulate and deposit in further distance where they may disseminate intravascular thrombosis in severe cases of disease. Thrombi may also facilitate leukocytes migration into alveoli where their accumulation and activation exacerbate cytokine storms and tissue damage, further complicating the disease. Based on these mechanisms, whether an effective anti-inflammatory protocol can prevent thrombotic events, or on the other hand; efficient antiplatelet or anticoagulant regimens may be associated with reduced cytokine storms and tissue damage, is now of interests for several ongoing researches. Thus shedding more light on platelet-leukocyte crosstalk, the review presented here discusses the detailed mechanisms by which platelets may contribute to the pathogenesis of COVID-19, especially in severe cases where their interaction with leukocytes can intensify both inflammatory state and thrombosis in a reciprocal manner.

Roles of the gut microbiota in severe SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The pathophysiological mechanisms linking gut dysbiosis and severe SARS-CoV-2 infection are poorly understood, although gut microbiota disorders are related to severe SARS-CoV-2 infections. The roles of the gut microbiota in severe SARS-CoV-2 infection were compared with those in respiratory viral infection, which is an easily understood and enlightening analogy. Secondary bacterial infections caused by immune disorders and antibiotic abuse can lead to dysregulation of the gut microbiota in patients with respiratory viral infections. The gut microbiota can influence the progression of respiratory viral infections through metabolites and the immune response, which is known as the gut-lung axis. Angiotensin-converting enzyme 2 is expressed in both the lungs and the small intestine, which may be a bridge between the lung and the gut. Similarly, SARS-CoV-2 infection has been shown to disturb the gut microbiota, which may be the cause of cytokine storms. Bacteria in the gut, lung, and other tissues and respiratory viruses can be considered microecosystems and may exert overall effects on the host. By referencing respiratory viral infections, this review focused on the mechanisms involved in the interaction between SARS-CoV-2 infections and the gut microbiota and provides new strategies for the treatment or prevention of severe SARS-CoV-2 infections by improving gut microbial homeostasis.

Nutritional fat modulation as a non-pharmacological approach to children infected with COVID-19, a challenge in food biochemistry

WHO confirmed that COVID-19 disease is a pandemic event on March 11, 2020. The causative organism is a new virus called SARS-CoV-2. The review aims to explore the effect of nutrition-in particular the fat component - on the COVID-19 course in pediatrics. In this review, I will explain the relationship between the dietary fat component and its role as a macronutrient in the modulation of the disease severity or the prevention. The modification could be in the type or the amount of the dietary fat. To illustrate, it is advisable to avoid the saturated and trans-fatty acids due to their links to obesity with subsequent raised risks for COVID-19. In addition, the amount of dietary fat can be ameliorated to yield better disease outcomes. To illustrate, the ketogenic diet (high fat diet) provides the betahydroxybutrate which has favorable effects on the immunity suppressing and delaying the cytokine storms. © 2022 National Information and Documentation Center (NIDOC).

IL-6 Revisited: From Rheumatoid Arthritis to CAR T Cell Therapy and COVID-19.

The diverse biological activity of interleukin-6 (IL-6) contributes to the maintenance of homeostasis. Emergent infection or tissue injury induces rapid production of IL-6 and activates host defense through augmentation of acute-phase proteins and immune responses. However, excessive IL-6 production and uncontrolled IL-6 receptor signaling are critical to pathogenesis. Over the years, therapeutic agents targeting IL-6 signaling, such as tocilizumab, a humanized anti-IL-6 receptor antibody, have shown remarkable efficacy for rheumatoid arthritis, Castleman disease, and juvenile idiopathic arthritis, and their efficacy in other diseases is continually being reported. Emerging evidence has demonstrated the benefit of tocilizumab for several types of acute inflammatory diseases, including cytokine storms induced by chimeric antigen receptor T cell therapy and coronavirus disease 2019 (COVID-19). Here, we refocus attention on the biology of IL-6 and summarize the distinct pathological roles of IL-6 signaling in several acute and chronic inflammatory diseases.

Autoimmune Hemolytic Anemia Exacerbation Associated With COVID-19 Infection and Markedly Elevated Inflammatory Markers.

The association between previously diagnosed autoimmune hemolytic anemia and exacerbations due to coronavirus disease 2019 (COVID-19) infection is a rare phenomenon that is not well understood. In this case, we present a 68-year-old female with a past medical history significant for systemic lupus erythematosus (SLE), splenectomy, and autoimmune hemolytic anemia (AIHA) since childhood that had been very well controlled with only one previous exacerbation. This patient's chief complaint and clinical symptoms at admission were related to hemolytic anemia and not active COVID-19 infection. This case report reveals a possible association between the hyperinflammatory syndrome caused by COVID-19 and the exacerbation of previously well-controlled autoimmune diseases.

A retrospective evaluation of COVID-19 patients treated with Tocilizumab: who should be treated?

INTRODUCTION: Tocilizumab, can be used in the treatment of COVID-19 in patients developing cytokine storms. This study retrospectively evaluated patients treated with Tocilizumab. METHODOLOGY: This study included 23 patients (17 men) admitted to the hospital and received Tocilizumab due to cytokine storms. The patients were categorized into three groups: "moderate, severe, and critical". Clinical outcomes after 7 days of hospitalization were classified as "death, disease aggravation, clinical stabilization, and clinical improvement". RESULTS: The mean age of the patients was 58±10.1 years. 52.2% of the patients were severely ill, and 47.8% were critically ill. After tocilizumab treatment, the mean lymphocyte count increased in all patients; the C-reactive protein levels dropped rapidly, except for one patient. After the first dose, the patients' fever dropped dramatically, and their oxygen support needs decreased. During the treatment, 82.6% of the patients were in the intensive care unit. At the end of the treatment, 56.5% had clinical improvement, 13% had clinical stabilization, and 4.3% had aggravation. Mortality occurred in 26.1%; 60.9% were discharged within a mean time of 19.14 ± 13.57 days after their treatment, and 18.2% of the critically ill and 91.7% of the severely ill patients recovered. CONCLUSIONS: Despite high rates of recovery and discharge after the tocilizumab treatment in the severely ill patients, more than half of the critically ill patients died. Early tocilizumab treatment resulted in a high survival rate and reduced the rates of progression to more critical states and mortality. Tocilizumab treatment should be given early in patients developing cytokine storms.

High-Dose Dexamethasone Versus Tocilizumab in Moderate to Severe COVID-19 Pneumonia: A Randomized Controlled Trial.

Background and objectives Recent randomized controlled trials (RCTs) have indicated potential therapeutic benefits with high-dose dexamethasone (HDD) or tocilizumab (TCZ) plus standard care in moderate to severe coronavirus disease 2019 (COVID-19) with acute respiratory distress syndrome (ARDS). No study has compared these two against each other. We aimed to compare the efficacy and safety of HDD against TCZ in moderate to severe COVID-ARDS. Methods Patients admitted with moderate to severe COVID-19 ARDS with clinical worsening within 48 hours of standard care were randomly assigned to receive either HDD or TCZ plus standard care. The primary outcome was ventilator-free days (VFDs) at 28 days. The main secondary outcomes were 28-day all-cause mortality and the incidence of adverse events. Our initial plan was to perform an interim analysis of the first 42 patients. Results VFDs were significantly lower in the HDD arm (median difference: 28 days; 95% confidence interval (CI): 19.35-36.65; Cohen's d = 1.14;p < 0.001). We stopped the trial at the first interim analysis due to high 28-day mortality in the HDD arm (relative risk (RR) of death: 6.5; p = 0.007; NNT (harm) = 1.91). The incidence of secondary infections was also significantly high in the HDD arm (RR: 5.5; p = 0.015; NNT (harm) = 2.33). Conclusions In our study population, HDD was associated with a very high rate of mortality and adverse events. We would not recommend HDD to mitigate the cytokine storm in moderate to severe COVID-19 ARDS. TCZ appears to be a much better and safer alternative.

Off balance: Interferons in COVID-19 lung infections.

Interferons are innate and adaptive cytokines involved in many biological responses, in particular, viral infections. With the final response the result of the balance of the different types of Interferons. Cytokine storms are physiological reactions observed in humans and animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules. The excessive and prolonged presence of these cytokines can cause tissue damage, multisystem organ failure and death. The role of Interferons in virus clearance, tissue damage and cytokine storms are discussed, in view of COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The imbalance of Type I, Type II and Type III Interferons during a viral infection contribute to the clinical outcome, possibly together with other cytokines, in particular, TNFα, with clear implications for clinical interventions to restore their correct balance.

Infrared light therapy relieves TLR-4 dependent hyper-inflammation of the type induced by COVID-19.

The leading cause of mortality from COVID-19 infection is respiratory distress due to an exaggerated host immune response, resulting in hyper-inflammation and ensuing cytokine storms in the lungs. Current drug-based therapies are of limited efficacy, costly, and have potential negative side effects. By contrast, photobiomodulation therapy, which involves periodic brief exposure to red or infrared light, is a noninvasive, safe, and affordable method that is currently being used to treat a wide range of diseases with underlying inflammatory conditions. Here, we show that exposure to two 10-min, high-intensity periods per day of infrared light causes a marked reduction in the TLR-4 dependent inflammatory response pathway, which has been implicated in the onset of cytokine storms in COVID-19 patients. Infrared light exposure resulted in a significant decline in NFkB and AP1 activity as measured by the reporter gene assay; decreased expression of inflammatory marker genes IL-6, IL-8, TNF-alpha, INF-alpha, and INF-beta as determined by qPCR gene expression assay; and an 80% decline in secreted cytokine IL6 as measured by ELISA assay in cultured human cells. All of these changes occurred after only 48 hours of treatment. We suggest that an underlying cellular mechanism involving modulation of ROS may downregulate the host immune response after Infrared Light exposure, leading to decrease in inflammation. We further discuss technical considerations involving light sources and exposure conditions to put these observations into potential clinical use to treat COVID-19 induced mortality.

Clinical efficacy and safety of combination therapy of tocilizumab and steroid pulse therapy for critical COVID-19 in HD patients.

BACKGROUND: Critical coronavirus disease 2019 (COVID-19) has a high fatality rate, especially in hemodialysis (HD) patients, with this poor prognosis being caused by systemic hyperinflammation; cytokine storms. Steroid pulse therapy or tocilizumab (TCZ) have insufficient inhibitory effects against cytokine storms in critical cases. This study evaluated the clinical effects and safety of combining steroid pulse therapy and TCZ. METHODS: From September 2020 to May 2021, 201 patients with COVID-19 were admitted to our hospital. Before February 2021, patients with an oxygen demand exceeding 8 L/min were intubated and treated with standard therapy (dexamethasone and antiviral therapy). After February 2021, patients underwent high-flow nasal cannula oxygen therapy and were treated with TCZ (8 mg/kg) and methylprednisolone (mPSL) (500 mg/day [≤ 75 kg], 1000 mg/day [> 75 kg]) for 3 days. We compared background characteristics, laboratory findings, and prognosis between non-HD and HD patients and between patients who received and did not receive TCZ and mPSL pulse therapy. RESULTS: Among non-HD patients, the TCZ + mPSL pulse group had significantly higher survival rates and lower secondary infection rates (p < 0.05), than the standard therapy group. All HD patients in the standard therapy group with oxygen demand exceeding 8 L/min died. Contrastingly, all patients in the TCZ + mPSL pulse group survived, with their oxygen demand decreasing to 0-1 L/min within 3 weeks post-administration. CONCLUSION: TCZ combined with mPSL pulse therapy improved the survival rate without significant adverse events in critical HD and non-HD patients with COVID-19 by strongly suppressing systemic hyperinflammation.

Coronavirus Disease 2019 Infection as a Risk Factor for Infective Endocarditis.

Infective endocarditis (IE) is associated with relatively high morbidity and mortality and several risk factors have been identified in the past. Several predisposing factors for IE have been recognized in the literature, depending on the type of bacteria. Coronavirus disease 2019 (COVID-19) infection causes coagulopathy-associated complications and damage to many organ systems due to the inflammatory response induced by this viral infection. COVID-19 emerged only about a year ago and there are many unknown post-COVID-19 complications at this time. Here, we present the case of Streptococcus mitis IE in a patient with no prior predisposing factors other than diagnosis with COVID-19 a month ago.

Cytokine Storm: The Primary Determinant for the Pathophysiological Evolution of COVID-19 Deterioration.

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an ongoing major threat to global health and has posed significant challenges for the treatment of severely ill COVID-19 patients. Several studies have reported that cytokine storms are an important cause of disease deterioration and death in COVID-19 patients. Consequently, it is important to understand the specific pathophysiological processes underlying how cytokine storms promote the deterioration of COVID-19. Here, we outline the pathophysiological processes through which cytokine storms contribute to the deterioration of SARS-CoV-2 infection and describe the interaction between SARS-CoV-2 and the immune system, as well as the pathophysiology of immune response dysfunction that leads to acute respiratory distress syndrome (ARDS), multi-organ dysfunction syndrome (MODS), and coagulation impairment. Treatments based on inhibiting cytokine storm-induced deterioration and occurrence are also described.

Therapeutic application of light and electromagnetic fields to reduce hyper-inflammation triggered by COVID-19.

COVID-19 - related morbidity is associated with exaggerated inflammation and cytokine production in the lungs, leading to acute respiratory failure. The cellular mechanisms underlying these so-called 'cytokine storms' are regulated through the Toll-like receptor 4 (TLR4) signaling pathway and by ROS (Reactive Oxygen Species). Both light (Photobiomodulation) and magnetic fields (e.g., Pulsed Electro Magnetic Field) stimulation are noninvasive therapies known to confer anti-inflammatory effects and regulate ROS signaling pathways. Here we show that daily exposure to two 10-minute intervals of moderate intensity infra-red light significantly lowered the inflammatory response induced via the TLR4 receptor signaling pathway in human cell cultures. Anti-inflammatory effects were likewise achieved by electromagnetic field exposure of cells to daily 10-minute intervals of either Pulsed Electromagnetic Fields (PEMF), or to Low-Level static magnetic fields. Because current illumination and electromagnetic field therapies have no known side effects, and are already approved for some medical uses, we have here developed protocols for verification in clinical trials of COVID-19 infection. These treatments are affordable, simple to implement, and may help to resolve the acute respiratory distress of COVID-19 patients both in the home and in the hospital.